Apoptotic cell suicide is a fundamentally important biological process that is required to maintain the integrity and homeostasis of multicellular organisms. Inappropriate apoptosis, however, underlies the etiology of many of the most intractable of human diseases. In only the last few years, many of the molecules that participate in a conserved biochemical pathway that mediates the highly ordered process of apoptotic cell suicide have been identified. At the heart of this pathway are a family of cysteine proteases, the xe2x80x98caspasesxe2x80x99, that are related to mammalian interleukin-1xcex2 converting enzyme (ICE/caspase-1) and to CED-3, the product of a gene that is necessary for apoptotic suicide in the nematode C. elegans (Nicholson et al., 1997, Trends Biochem Sci 22:299-306). The role of these proteases in cell suicide is to disable critical homeostatic and repair processes as well as to cleave key structural components, resulting in the systematic and orderly disassembly of the dying cell.
The central importance of caspases in these processes has been demonstrated with both macromolecular and peptide-based inhibitors (which prevent apoptosis from occurring in vitro and in vivo) as well as by genetic approaches. Inhibition of apoptosis via attenuation of caspase activity should therefore be useful in the treatment of human diseases where inappropriate apoptosis is prominent or contributes to disease pathogenesis. Caspase inhibitors would thus be useful for the treatment of human diseases including, but not limited to, acute disorders such as cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, as well as chronic disorders such as neurodegenerative diseases (e.g. Alzheimer""s, polyglutamine-repeat disorders, Down""s, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HIV), diabetes, alopecia and aging.
Ten caspases have so far been identified in human cells. Each is synthesized as a catalytically dormant proenzyme containing an amino-terminal rodomain followed by the large and small subunits of the heterodimeric active enzyme. The subunits are excised from the proenzyme by cleavage at Asp-X unctions (Nicholson et al., 1997, Trends Biochem Sci 22:299-306). The strict requirement by caspases for Asp in the P1 position of substrates is consistent with a mechanism whereby proenzyme maturation can be either autocatalytic or performed by other caspases. The three dimensional crystal structures of mature caspase-1 and -3 show that the large subunit contains the principle components of the catalytic machinery, including the active site Cys residue which is harbored within the conserved pentapeptide motif, QACxc3x97G,1 and residues that stabilize the oxyanion of the tetrahedral transition state (Wilson et al., 1994, Nature 370:270-75; Walker et al., 1994, Cell 78:342-52; Rotonda et al., 1996, Nat Struct Biol 3:619-25). Both subunits contribute residues which stabilize the P1 Asp of substrates while the small subunit appears to contain most of the determinants that dictate substrate specificity and, in particular, those which form the specificity-determining S4 subsite. One distinctive feature of these proteases is the absolute requirement for an aspartic acid residue in the substrate P1 position. The carboxylate side chain of the substrate P1 Asp is tethered by four residues in caspase-1 (Arg179, Gln238 from p20 and Arg341, Ser347 from p10) that are absolutely conserved in all caspase family members. Catalysis involves a typical cysteine protease mechanism involving a catalytic dyad, composed of His237 and Cys285 (contained within an absolutely conserved QACxc3x97G pentapeptide) and an xe2x80x98oxyanion holexe2x80x99 involving Gly238 and Cys285. Inhibitors bind, however, in an unexpected non-transition state configuration (which raises important considerations for inhibitor design) with the oxyanion of the thiohemiacetal being stabilized by the active site His237.
Members of the caspase family can be divided into three functional subgroups based on their substrate specificities which have been defined by a positional-scanning combinatorial substrate approach. The principle effectors of apoptosis (group II caspases, which include caspases-2, -3 and -7 as well as C. elegans CED-3) have specificity for [P4]DExc3x97D[P1], a motif found at the cleavage site of most proteins known to be cleaved during apoptosis. On the other hand, the specificity of group mH caspases (caspases-6, -8, -9 and -10, as well as CTL-derived granzyme B) is [P4](I,V,L)Exc3x97D[P1] which corresponds to the activation site at the junction between the large and small subunits of other caspase proenzymes including group II (effector) family members. This and other evidence indicates that group III caspases function as upstream activators of group II caspases in a proteolytic cascade that amplifies the death signal. The role of group I caspases (caspases-1, -4 and -5) appears to be to mediate cytokine maturation and their role in apoptosis, if any, has not been substantiated.
A tetrapeptide corresponding to the substrate P4-P1 residues is sufficient for specific recognition by caspases and as a consequence has formed the basis for inhibitor design. In addition to the requirement for a P1 Asp, the P4 residue in particular appears to be most important for substrate recognition and specificity. Caspase-1, for example, prefers a hydrophobic residue such as Tyr in P4 (which corresponds to its YVHD cleavage site within proIL-1xcex2) whereas caspase-3 (and other group II enzymes) has a preference for an anionic Asp residue (which corresponds to the DXXD cleavage sites within most polypeptides that are cleaved by these enzymes during apoptosis). Peptide aldehydes, nitriles and ketones are potent reversible inhibitors of these proteases while compounds that form thiomethylketone adducts with the active site cysteine (e.g. peptide (acyloxy)methylketones) are potent irreversible inhibitors. For example, the tetrapeptide aldehyde Ac-YVAD-CHO (which was designed to mimic the YVHD caspase-1 recognition sequence within proIL-1) is a potent inhibitor of caspase-1 (Ki less than 1 nM) but a poor inhibitor of caspase-3 (Ki=12 xcexcM) (Thornberry et al., 1992, Nature 356:768-74). In contrast, the Ac-DEVD-CHO tetrapeptide aldehyde (which was designed to mimic the caspase-3 recognition site) is a very potent inhibitor of caspase-3 (Ki less than 1 nM) although it is also a weaker but reasonable inhibitor of caspase-1, presumably owing to promiscuity in the S4 subsite of this enzyme (Nicholson et al., 1995, Nature 376:37-43).
Several features plague these peptide-derived inhibitors as a platform for drug design. In addition to their metabolic instability and membrane impermeability, the slow-binding time-dependent inhibition of activity (e.g. kon caspase-1:Ac-YVAD-CHO=3.8xc3x97105 M-1s-1; kon caspase-3:Ac-DEVD-CHO=1.3xc3x97105 M-1s-1) precludes them from the rapid inhibition characteristics that may be necessary to abolish enzymatic activity in vivo. The present patent application describes the resolution of this issue with the discovery of several novel gamma-ketoacids that make highly suitable caspase inhibitors.
This invention encompasses the novel compounds of Formula I: 
or a pharmaceutically acceptable salt, ester or hydrate thereof, wherein:
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(O)CH2xe2x80x94;
Z is selected from the group consisting of:
(1) H,
(2) C1-11alkyl,
(3) C3-11cycloalkyl or a benzofused analog thereof,
(4) phenyl or naphthyl, and
(5) HET1, wherein HET1 represents a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N,
groups (2), (3) and (5) above are optionally substituted with 1-2 oxo groups,
groups (2)-(5) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo
(b) nitro,
(c) hydroxy,
(d) C1-4alkyl,
(e) C1-4alkoxy,
(f) C1-4alkylthio,
(g) C3-6cycloalkyl,
(h) phenyl or naphthyl,
(i) phenoxy,
(j) benzyl,
(k) benzyloxy, and
(l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
groups (h)-(1) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and
group (4) is further optionally substituted up to its maximum with halo groups;
R1 and R2 are independently selected from the group consisting of:
(1) H,
(2) halo,
(3) hydroxy,
(4) nitro,
(5) cyano,
(6) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, xe2x80x94S(O)0-2C1-10alkyl or xe2x80x94NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) hydroxy
(c) cyano,
(d) C1-4alkoxy,
(e) xe2x80x94NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
(f) xe2x80x94S(O)0-2C1-4alkyl, and
(g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
(7) phenoxy or xe2x80x94S(O)0-2phenyl,
(8) benzyloxy or xe2x80x94S(O)0-2benzyl,
(9) benzoyl,
(10) phenyl or naphthyl,
(11) xe2x80x94O-HET2 or xe2x80x94S-HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
(12) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below,
groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of: halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups;
or R1 and R2 may be taken in combination and represent a fused ring as shown below: 
xe2x80x83wherein Y and X are independently selected from the group consisting of xe2x80x94C(R10)2, xe2x80x94C(R10)2C(R10)2xe2x80x94, NR11xe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94, R3 is as defined below, each R9 is independently selected from H and C1-4alkyl, each R10 is independently selected from H and C1-4alkyl, and R11 is H or C1-4alkyl, or one R9 may be joined with either one R10 or R 11 on an adjacent atom to form a double bond;
R3 is C1-10alkyl, optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) hydroxy
(c) cyano,
(d) C1-4alkoxy,
(e) xe2x80x94NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
(f) xe2x80x94S(O)0-2C1-4alkyl, and
(g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
each R4 is independently selected from the group consisting of: H, halo, hydroxy, C1-6alkyl and C1-4alkoxy, said C1-6alkyl and C1-4alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halo groups; and
R5 is selected from the group consisting of: H, phenyl, naphthyl, C1-6alkyl optionally substituted with OR12 and 1-3 halo groups, and C57cycloalkyl optionally containing one heteroatom selected from O, S and NR13,
wherein R12 is selected from the group consisting of: H, C1-5alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C1-4alkyl and C1-4alkoxy, and
R13 is H or C1-4alkyl optionally substituted with 1-3 halo groups; and
R6 represents H;
or in the alternative, R5 and R6 are taken in combination and represent a ring of 4-7 members, said ring optionally containing one heteroatom selected from O, S and NR13.
The invention also encompasses pharmaceutical compositions containing a compound of Formula I as well as methods for treating caspase-3 mediated diseases.
The present invention encompasses compounds of Formula I: 
or a pharmaceutically acceptable salt, ester or hydrate thereof, wherein:
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94 or C(O)CH2xe2x80x94;
Z is selected from the group consisting of:
(1) H,
(2) C1-11alkyl,
(3) C3-11cycloalkyl or a benzofused analog thereof,
(4) phenyl or naphthyl, and
(5) HET1, wherein HET1 represents a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N,
groups (2), (3) and (5) above are optionally substituted with 1-2 oxo groups,
groups (2)-(5) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo
(b) nitro,
(c) hydroxy,
(d) C1-4alkyl,
(e) C1-4alkoxy,
(f) C1-4alkylthio,
(g) C3-6cycloalkyl,
(h) phenyl or naphthyl,
(i) phenoxy,
(j) benzyl,
(k) benzyloxy, and
(l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
groups (h)-(1) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and
group (4) is further optionally substituted up to its maximum with halo groups; R1 and R2 are independently selected from the group consisting of:
(1) H,
(2) halo,
(3) hydroxy,
(4) nitro,
(5) cyano,
(6) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, xe2x80x94S(O)0-2C1-10alkyl or xe2x80x94NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) hydroxy
(c) cyano,
(d) C1-4alkoxy,
(e) xe2x80x94NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
(f) xe2x80x94S(O)0-2C1-4alkyl, and
(g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C s5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
(7) phenoxy or xe2x80x94S(O)0-2phenyl,
(8) benzyloxy or xe2x80x94S(O)0-2benzyl,
(9) benzoyl,
(10) phenyl or naphthyl,
(11) xe2x80x94O-HET2 or xe2x80x94S-HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
(12) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below,
groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of: halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups;
or R1 and R2 may be taken in combination and represent a fused ring as shown below: 
xe2x80x83wherein Y and X are independently selected from the group consisting of xe2x80x94C(R10)2, xe2x80x94C(R10)2C(R10)2xe2x80x94, xe2x80x94NR11xe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94, R3 is as defined below, each R9 is independently selected from H and C1-4alkyl, each R10 is independently selected from H and C1-4alkyl, and R11 is H or C1-4alkyl, or one R9 may be joined with either one R10 or R11 on an adjacent atom to form a double bond;
R3 is C1-10alkyl, optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) hydroxy
(c) cyano,
(d) C1-4alkoxy,
(e) xe2x80x94NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
(f) xe2x80x94S(O)0-2C1-4alkyl, and
(g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
each R4 is independently selected from the group consisting of: H, halo, hydroxy, C1-6alkyl and C1-4alkoxy, said C1-6alkyl and C1-4alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halo groups; and
R5 is selected from the group consisting of: H, phenyl, naphthyl, C1-6alkyl optionally substituted with OR12 and 1-3 halo groups, and C5-7cycloalkyl optionally containing one heteroatom selected from O, S and NR13,
wherein R12 is selected from the group consisting of: H, C1-5alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C1-4alkyl and C1-4alkoxy, and
R13 is H or C1-4alkyl optionally substituted with 1-3 halo groups; and
R6 represents H;
or in the alternative, R5 and R6 are taken in combination and represent a ring of 4-7 members, said ring optionally containing one heteroatom selected from O, S and NR13.
An embodiment of the invention encompasses compounds of Formula I wherein R1 is selected from the group consisting of:
(1) halo,
(2) hydroxy,
(3) nitro,
(4) cyano,
(5) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, xe2x80x94S(O)0-2C1-10alkyl or xe2x80x94NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) hydroxy
(c) cyano,
(d) C1-4alkoxy,
(e) xe2x80x94NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
(f) xe2x80x94S(O)0-2C1-4alkyl, and
(g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
(6) phenoxy or xe2x80x94S(O)0-2phenyl,
(7) benzyloxy or xe2x80x94S(O)0-2benzyl,
(8) benzoyl,
(9) phenyl or naphthyl,
(10) xe2x80x94O-HET2 or xe2x80x94S-HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
(11) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below, and groups (6)-(11) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of: halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups.
An embodiment of the invention encompasses compounds of Formula I wherein R3 is methyl, optionally substituted with 1-3 halo groups.
Another embodiment of the invention encompasses compounds of Formula I wherein one R4 is hydroxy and the other R4 is H.
Another embodiment of the invention encompasses compounds of Formula I wherein R5 is isopropyl and R6 is H.
Another embodiment of the invention encompasses compounds of Formula I wherein W is a bond. Another embodiment of the invention encompasses compounds of Formula I wherein W is xe2x80x94CH2xe2x80x94. Another embodiment of the invention encompasses compounds of Formula I wherein W is xe2x80x94C(O)xe2x80x94. Another embodiment of the invention encompasses compounds of Formula I wherein W is C(O)CH2xe2x80x94.
Another embodiment of the invention encompasses compounds of Formula I wherein Z is phenyl or naphthyl, wherein: said phenyl or naphthyl is optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) nitro,
(b) hydroxy,
(c) C1-4alkyl,
(d) C1-4alkoxy,
(e) C1-4alkylthio,
(f) C3-6cycloalkyl,
(g) phenyl or naphthyl,
(h) phenoxy,
(i) benzyl,
(l) benzyloxy, and
(k) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy, groups (g)-(k) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and said phenyl or naphthyl is further optionally substituted up to its maximum with halo groups.
Another embodiment of the invention encompasses compounds of Formula I wherein Z is C1-11alkyl, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo
(b) nitro,
(c) hydroxy,
(d) C1-4alkyl,
(e) C1-4alkoxy,
(f) C1-4alkylthio,
(g) C3-6cycloalkyl,
(h) phenyl or naphthyl,
(i) phenoxy,
(j) benzyl,
(k) benzyloxy, and
(l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy and groups (h)-(1) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl.
Another embodiment of the invention encompasses compounds of Formula I wherein Z is C3-11cycloalkyl or a benzofused analog thereof, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo
(b) nitro,
(c) hydroxy,
(d) C1-4alkyl,
(e) C1-4alkoxy,
(f) C1-4alkylthio,
(g) C3-6cycloalkyl,
(h) phenyl or naphthyl,
(i) phenoxy,
(j) benzyl,
(k) benzyloxy, and
(l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy, and groups (h)-(1) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl.
Another embodiment of the invention encompasses compounds of Formula I wherein Z is HET1, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo
(b) nitro,
(c) hydroxy,
(d) C1-4alkyl,
(e) C1-4alkoxy,
(f) C1-4alkylthio,
(g) C3-6cycloalkyl,
(h) phenyl or naphthyl,
(i) phenoxy,
(j) benzyl,
(k) benzyloxy, and
(l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy, and groups (h)-(k) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl.
Another embodiment of the invention encompasses compounds of Formula I wherein HET1 represents a member selected from the group consisting of: pyridine, pyrimidine, pyridazine, pyrazine, furan, thiophene, thiazole and oxazole, or a benzofused analog thereof, each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) nitro,
(c) C1-4alkyl,
(d) C1-4alkoxy,
(e) C1-4alkylthio,
(f) C3-6cycloalkyl,
(g) phenoxy,
(h) benzyl,
(i) benzyloxy, and
(j) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy, and groups (g)-(j) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl.
Another embodiment of the invention encompasses compounds of Formula I wherein HET2 is selected from the group consisting of: butyrolactone, tetrahydrofuran, tetrahydropyran, 2-pyrrolidinone, pyridine and pyrimidine, each optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups.
Another embodiment of the invention encompasses compounds of Formula I wherein HET3 is selected from the group consisting of: 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, thiophene, pyrrole, pyridine, tetrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole and 1,3,4-triazole, each optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups.
Another embodiment of the invention encompasses compounds of formula I wherein:
W is a bond, xe2x80x94CH2xe2x80x94, (O)xe2x80x94 or xe2x80x94C(O)CH2xe2x80x94;
Z is selected from the group consisting of:
(1) C5-6cycloalkyl or a benzofused analog thereof,
(2) phenyl or naphthyl, and
(3) HET1, wherein HET1 represents a 5- to 10-membered mono-bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 3 heteroatoms selected from O, S and N, wherein:
groups (1) and (3) above are optionally substituted with 1-2 oxo groups;
groups (1), (2) and (3) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) nitro,
(c) C1-4alkyl,
(d) C1-4alkoxy,
(e) C1-4alkylthio,
(f) C3-6cycloalkyl,
(g) phenoxy,
(h) benzyl,
(i) benzyloxy, and
(j) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
groups (g)-(j) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and
group (2) is further optionally substituted up to its maximum with halo groups;
R1 is selected from the group consisting of:
(1) halo,
(2) C1-4alkyl or C1-4alkoxy, each optionally substituted with oxo and 1-3 halo groups, and
(3) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, and optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
R2 is H,
R3 is C1-4alkyl, optionally substituted with 1-3 halo groups and further optionally substituted with oxo or xe2x80x94NHR7 or both, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with xe2x80x94NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with 
xe2x80x83and
each R4 is independently selected from the group consisting of: H and hydroxy.
Within this embodiment there is a class of compounds of Formula I wherein R5 is isopropyl and R6 is H.
Within this class, there is a subclass of compounds of Formula I wherein: HET1 is selected from the group consisting of:
(1) pyridine, pyridazine, pyrimidine or pyrazine, or a benzofused analog thereof, each optionally substituted with 1-3 substituents independently selected from the group consisting of:
(a) halo,
(b) nitro,
(c) C1-4alkyl,
(d) C1-4alkoxy,
(e) C1-4alkylthio,
(f) C3-6cycloalkyl,
(g) phenoxy,
(h) benzyl,
(i) benzyloxy, and
(j) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
groups (g)-(j) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, 
HET3 is 1,2,4-oxadiazole, optionally substituted with C1-4alkyl.
For purposes of this specification alkyl means linear or branched structures and combinations thereof, containing one to twenty carbon atoms unless otherwise specified. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, and the like.
Cycloalkyl means cyclic structures, optionally combined with linear or branched structures, containing one to twenty carbon atoms unless otherwise specified. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1- bicyclo[4.4.0]decyl and the like.
Alkoxy means alkoxy groups of one to ten carbon atoms, unless otherwise specified, of a straight, branched or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and the like.
Alkylthio means alkylthio groups of one to ten carbon atoms, unless otherwise specified, of a straight, branched or cyclic configuration. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, etc. By way of illustration, the propylthio group signifies xe2x80x94SCH2CH2CH3.
Halo includes F, Cl, Br and I.
Examples of HET1 include pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole and oxazole.
Examples of HET2 include butyrolactone, tetrahydrofuran, tetrahydropyran, 2-pyrrolidinone, pyridine and pyrimidine.
Examples of HET3 include 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, thiophene, pyrrole, pyridine, tetrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole and 1,3,4-triazole.
For purposes of this specification, the following abbreviations have the indicated meanings:
Alkyl group abbreviations:

Representative examples of compounds of Formula I are found in Table I below.
The compounds described herein, and in particular, in Table I, are intended to include salts, enantiomers, esters and hydrates, in pure form and as a mixture thereof. Also, when a nitrogen atom appears, it is understood sufficient hydrogen atoms are present to satisfy the valency of the nitrogen atom.
While chiral structures are shown below, by substituting into the synthesis schemes an enantiomer other than the one shown, or by substituting into the schemes a mixture of enantiomers, a different isomer or a racemic mixture can be achieved. Thus, all such isomers and mixtures are included in the present invention.
The compounds described typically contain asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
This invention also encompasses a pharmaceutical composition comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
This invention also encompasses a method of treating or preventing a caspase-3 mediated disease or condition in a mammalian patient in need of such treatment, comprising administering to said patient a compound of Formula I in an amount effective to treat or prevent said caspase-3 mediated disease.
Another embodiment of the invention encompasses the method of treating or preventing a caspase-3 mediated disease wherein the disease or condition is selected from the group consisting of:
cardiac or cerebral ischemia/reperfusion injury, type I diabetes, immune deficiency syndrome, AIDS, cerebral and spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson""s disease, Alzheimer""s disease, Down""s syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders.
Another embodiment of the invention encompasses the method of treating or preventing a caspase-3 mediated disease wherein the disease or condition is selected from cardiac and cerebral ischemia/reperfusion injury, spinal cord injury and organ damage during transplantation.
Another embodiment of the invention encompasses the method of treating or preventing a caspase-3 mediated disease wherein the disease or condition is a chronic disorder selected from the group consisting of: a neurodegenerative disease selected from Alzheimer""s, polyglutamine-repeat disorders, Down""s syndrome, spinal muscular atrophy, multiple sclerosis, immunodeficiency, HIV, diabetes, alopecia and aging.
Another embodiment of the invention encompasses the method of treating or preventing a caspase-3 mediated disease wherein the disease or condition is selected from the group consisting of: cardiac or cerebral ischemia or reperfusion injury, type I diabetes, immune deficiency syndrome or AIDS, cerebral or spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson""s disease, Alzheimer""s disease, Down""s syndrome, spinal muscular atrophy, multiple sclerosis, neurodegenerative disorders, sepsis and bacterial meningitis.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases. Representative salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, ammonium, potassium, sodium, zinc and the like. Particularly preferred are the calcium, magnesium, potassium, and sodium salts. Representative salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabarnine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometharnine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
In the discussion of methods of treatment that follows, reference to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The ability of the compounds of Formula I to inhibit caspase-3 make them useful research tools in the field of apoptosis.
The magnitude of therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration and vary upon the clinician""s judgement. It will also vary according to the age, weight and response of the individual patient. An effective dosage amount of the active component can thus be determined by the clinician after a consideration of all the criteria and using is best judgement on the patient""s behalf. A representative dose will range from 0.001 mpk/d to about 100 mpk/d.
An ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
Any suitable route of administration may be employed for providing an effective dosage of a compound of the present invention. For example, oral, parenteral and topical may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The compositions include compositions suitable for oral, parenteral and ocular (ophthalmic). They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, alcohols, oils, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case or oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. For example, each dosage unit may contain from about 0.01 mg to about 1.0 g of the active ingredient.
The compounds of the present invention are prepared using the general procedures described below: 
Bromomethyl ketone 1 is prepared as illustrated in Scheme 1. Reaction of N-fluorenylmethyloxycarbonyl-L-aspartic acid xcex2-tert-butyl ester (Fmoc-L-Asp (OtBu)xe2x80x94OH) (2) (Novabiochem) with iso-butyl chloroformate (IBCF) followed by treating the reaction mixture with an excess of diazomethane yields the diazomethyl ketone intermediate 3. This intermediate is subjected in situ to a 1:1 mixture of AcOH and 45% aqueous hydrobromic acid (HBr) to give compound 1 as a white powder. 
The semicarbazide Resin A is prepared according to Scheme 2. Treatment of compound 4 (Webb et al, J. Am. Chem. Soc. 114, 3156 (1992)) with a commercial amino-Merrifield resin in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT) in dichloromethane followed by removal of the Boc group with trifluoroacetic acid (TFA) in dichloromethane afforded Resin A. 
The general procedure for solid phase synthesis of dipeptide I incorporating either a phenoxide P1xe2x80x2 side chain or a P1xe2x80x2 carboxylate side chain is illustrated in Scheme 3. Bromomethyl ketone 1 is reacted with Resin A in THF in the presence of acetic acid to afford Resin B, which is reacted with a phenol or a carboxylic acid in the presence of suitable bases such as potassium fluoride (KF) or Cs2CO3 in DMF to give Resin C. The Fmoc group in Resin C is removed with 20% (v) piperidine (Pip) in DMF and the resultant resin reacted with FmocHNCR5(R6)COOH using O-(7-Azabenzotriazol-1-yl)N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU) as the activating agent and diisopropylethylamine (DIEA) as the base, affording Resin D. The Fmoc group in Resin D is cleaved similarly and then the amino group released is reacted with acid 5 as shown to yield Resin E. The final dipeptide I is released from the solid support by treating Resin D with trifluoroacetic acid (TFA) in water (9/1, v/v). This scheme does not enable the preparation of certain P1xe2x80x2 carboxylate analogs. 
The solution phase synthesis of compound I is outlined in Scheme 4. Acid 5 is first reacted with an appropriate amine 6 using EDCI as the coupling reagent to give amide 7. The t-butyl ester in 7 is cleaved with trifluoroacetic acid to yield carboxylic acid 8, which is further reacted with xcex2-t-butyl aspartic acid methyl ester (9) in the presence of HATU and diisopropylethylamine, giving product 10. The methyl ester in is hydrolyzed using LiOH in ThF and acid 11 thus obtained is reacted with iso-butyl chloroformate in the presence of N-methylmorpholine. The mixed anhydride thus generated is reacted with diazomethane in situ. The mixture is then treated with a solution of 45% HBr in glacial acetic acid (1:1, v/v) to afford bromomethyl ketone 12. Reaction of 12 with a suitable phenol or carboxylic acid in the presence of bases such as KF or Cs2CO3 followed by cleavage of the t-butyl ester with TFA furnish the final product I.